Dengue is a mosquito-borne flavivirus that is spreading at an unprecedented rate and has developed into a major health and economic burden in over 50 countries. Current DENV vaccines protecting against all four DENV serotypes must be delivered as a “tetravalent” formulation of four viruses or four recombinant proteins, each intended to confer protection against that serotype. The correct mix of serotypes in the tetravalent cocktail to achieve a balanced antibody response is not known, underscored by the recent failure of the most advanced tetravalent live attenuated chimeric virus to provide clinically meaningful protection in a large phase 2B trial in Thailand (Sabchareon A, et al., 2012). Viral interference is thought to contribute to failure as one or more virus serotypes out-compete the others. The DENV-1/3 and DENY 3/1 chimeric viruses are single viruses that present epitopes recognized by neutralizing antibodies from both DENV-1 and DENV-3 immune individuals. This indicates that single viruses should be able to elicit neutralizing antibodies targeting two serotypes at once, replacing two viruses (DENV-1 and 3) with one virus (DENV-1/3 or DENV-3/1).